To assess the anti-tumor activity of LGX818/MEK162 in combination with third targeted agents after progression on LGX818/MEK162 combination therapy.
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall response rate (ORR) of LGX818/MEK162 in combination with third targeted
agents after progression on LGX818/MEK162 combination therapy.
Secondary outcome
Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 of Combination Part
(Part II)
Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry
values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions
and dose intensity.
Background summary
Melanoma is one of the most aggressive human malignancies. Its incidence has
rapidly increased throughout the world in the last few decades faster than
that of all solid tumors. Although the majority of early stage patients can be
treated with surgical resection, and have excellent survival rates, many will
develop disseminated disease. The prognosis for patients with distant
metastasis is, by contrast, very poor.
Currently, the existing therapeutic options for patients with melanoma comprise
of 6 FDA approved therapies: dacarbazine (DTIC), interleukin-2 (IL-2),
ipilimumab (anti-CTLA-4) ,vemurafenib and dabrafenib (BRAF inhibitors) as well
as trametinib (MEK inhibitor).
In addition to approved therapies, the concept of a simultaneous, dual,
vertical pathway inhibition of the RAF/MEK/ERK pathway to prevent the emergence
of resistance to single agent is currently being explored by the combination
treatment of a selective BRAF- and a MEK1/2-inhibitor.
Despite the demonstrated clinical efficacy of BRAF and MEK inhibitors, in most
cases tumors become resistant to treatment.
activation of survival pathways have also been demonstrated to confer
resistance to BRAF inhibitors, and by extension are likely to promote
resistance to combinations of BRAF and MEK inhibitors as well. It is important
of identifying mechanisms of resistance in real time in order to initiate
rational combination therapy soon after progression. By comparing the set of
genetic alterations present in a progressing tumor at the time of relapse to
the alterations present in the tumor prior to treatment, it should be possible
to identify the likely molecular mechanisms underlying resistance. This
comparison could then be used to direct the selection of a drug combination
therapy for an individual patient that is most likely to overcome resistance.
In this CLGX818X2109 study, a rational combination treatment approach informed
by comparing the genetic profiles of relapsed and treatment naive tumors will
be taken to expand and improve the therapeutic options for patients with
BRAF-mutant advanced or metastatic melanoma
Study objective
To assess the anti-tumor activity of LGX818/MEK162 in combination with third
targeted agents after progression on LGX818/MEK162 combination therapy.
Study design
multicenter, open-label, phase II
two parts:
Part I, patients naïve to selective BRAF and MEK inhibitors will be treated
with the LGX818/MEK162 combination Based on the genetic assessment of a tumor
biopsy obtained at progression of disease (PD), patients will enter Part II of
the study for tailored combination treatment in one of four arms: LGX818/MEK162
+ BKM120, BGJ398, INC280 or LEE011
New triple combination arms will be introduced in the study via substantial
protocol amendment
During Part I, patients will be treated with LGX818/MEK162 at RP2D of the dual
combination.
In Part II, dose escalation for the triple combination will occur unless a RP2D
for the respective combination is already established.
Non-naïve patients for BRAF and/or MEK inhibitor treatment who are relapsing
will be enrolled into Part II. Depending on the previous treatment, patients
may receive a brief Run-in with LGX818/MEK162 combination.
Intervention
Part I : dual combination LGX818 (QD) and MEK162 (BID)
Part II: triple combination of MEK162 and LGX818 (see above) and logic third
compound
• LGX818 (QD) and MEK162 (BID) and BKM120 (QD)
• LGX818 (QD) and MEK162 (BID) and BGJ398 (QD)
• LGX818 (QD) and MEK162 (BID) and INC280 (BID)
• LGX818 (QD) and MEK162 (BID) and LEE011 (QD)
Study burden and risks
Risks and burden are stronlgly depended on the group (Part I) en treatment arm
(Part II) the patient will be treated in. Also the cycle number is relevant.
Below this has not been indicated specifically:
Risks: toxicities of the medication
BurdenL cycles of 21 days or 28 days, with 1,2,3,4 or 5 visites per cycle.
Blooddraws as specified in section J, inclusive PK sampling
ECGs
MUGA scan and CT scan (see section J)
Tumor biopsies
Ophthamological assessments
skintest
Walnut Street, 3200
Boulder CO 80301
US
Walnut Street, 3200
Boulder CO 80301
US
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years at the start of dosing
2. Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma (stage IIIC to IV per American Joint Committee on Cancer [AJCC]).
3. Documented evidence of BRAF V600 mutation
4. Evidence of measurable disease, as determined by RECIST v1.1.
5. ECOG Performance Status <= 2.
6. Negative serum pregnancy test within 72 hours prior to the first dose of study treatment in all women of childbearing potential.
7. For Group A only: patients who are naïve to selective BRAF and MEK inhibitors and might have received other allowed treatments
8. For Group A only: Patients must provide either archival or newly obtained tumor sample at baseline. In addition, patients must agree to a mandatory biopsy at the time of progression from LGX818/MEK162 combination, if not medically contraindicated.
9. For Group B only: Patients with progressive disease following any single or double-agent BRAF and MEK inhibitors other than LGX818/MEK162
10. For Group B only: The most recent biopsy sample collected after progression from any BRAF and/or MEK inhibitor (other than LGX818 and MEK162 combination) must be available before entering the Run-in. In addition, patients must agree to a biopsy at the time of progression from LGX818/MEK162 combination if necessary and not medically contraindicated.
11. For Group C only Progressive disease documented per RECIST v 1.1 and determined using radiological assessments, following prior treatment with LGX818/MEK162 combination.
12. For Group C only A pre-LGX818/MEK162 combination archival tumor sample must be available.
13. For Group C only A biopsy sample at disease progression, post-LGX818/MEK162 combination, must be either already available from previous studies or collectable at screening/baseline of this study..
14 Able to understand and voluntarily sign the informed consent form prior to any screening procedure, and ability to comply with the study visit schedule and other protocol requirements.
15. For Group B only: Patients who progressed after treatment with single agent BRAF or MEK inhibitor or the combination of BRAF/MEK inhibitors (excluding LGX818/MEK162 combination) and patients who did not progress on their prior BRAF and/or MEK inhibitor regimen (including LGX818 and/or MEK162 inhibitor), but did not tolerate this treatment, may enter the Run-in (Group B) upon consultation with Sponsor.
Exclusion criteria
Part I and Run-in
1. Symptomatic or untreated leptomeningeal disease.
2. Symptomatic brain metastasis.
3. Known acute or chronic pancreatitis.
4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO
5 Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery.;PART II
Patients are NOT eligible for enrollment in Part II of this study if they meet any exclusion criteria listed above, and all the applicable additional exclusion criteria listed below.
1. Patients who discontinued LGX818/MEK162 for more than 6 weeks prior to the scheduled first dose of triple combination (Part II), and AEs related to the above treatment are not resolved to at least grade 2.;Additional Exclusion Criteria for Part II for selected triple combination may apply. Please refer to the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004552-38-NL |
| CCMO | NL48488.031.14 |